C/EBPα and the pathophysiology of acute myeloid leukemia

Purpose of review. The transcription factor C/EBP alpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPa function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPa alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBP alpha function and the development of the disorder. Recent findings. Conditional mouse models provide direct evidence that loss of C/EBPa function leads to the accumulation of myeloid blasts in the bone marrow. Targeted disruption of the wild type C/EBPa protein, while conserving the dominant-negative 30 kDa isoform of C/EBP alpha, induces an AML-like disease in mice. In hematopoietic stem cells C/EBP alpha serves to limit cell self-renewal. Finally, C/EBP alpha function is disrupted at different levels in specific subgroups of acute myeloid leukemia patients. Summary. There is evidence that impaired C/EBP alpha function contributes directly to the development of acute myeloid leukemia, Normal myeloid development and acute myeloid leukemia are now thought to reflect opposite sides of the same hematopoietic coin. Restoring C/EBPa function represents a promising target for novel therapeutic strategies in acute myeloid leukemia patients.